Evaluation of the Safety,Tolerability, Pharmacokinetics, and Pharmacodynamics of Long-term Mitapivat Dosing in Subjects With Stable Sickle Cell Disease: An Extension of a Phase I Pilot Study of Mitapivat

  • End date
    Oct 19, 2023
  • participants needed
  • sponsor
    National Heart, Lung, and Blood Institute (NHLBI)
Updated on 21 September 2022
platelet count
absolute neutrophil count
glomerular filtration rate
blood transfusion
a hemoglobin
acute pain



Sickle cell disease (SCD) is a disorder that causes episodes of acute pain and progressive organ damage. Ways to manage SCD have evolved slowly. Treatments do not always work. Researchers want to see if a drug called mitapivat can help people with SCD.


To test the long-term tolerability and safety of mitapivat (or AG-348) in people with SCD.


Adults age 18-70 with SCD who took part in and benefited from NIH study #19H0097.


Participants will be screened with a medical history and physical exam. They will give a blood sample. They will have an electrocardiogram to test heart function.

Participants will repeat some of the screening tests during the study.

Participants will complete 6-minute walk tests to measure mobility and function. They will have transthoracic echocardiograms to measure heart and lung function. They will have dual-energy X-ray absorptiometry scans to measure bone health. They will complete online questionnaires that measure their overall health and well-being.

Participants will take the study drug in the form of a tablet twice a day.

Participants will keep a study diary. They will record any symptoms they may have.

Participation will last for about 54 weeks. After 48 weeks, participants can either keep taking the study drug for 48 more weeks or be tapered off of the study drug to complete the study. Those who are on the study for 1 year will have 10 study visits. Those who are on the study for 2 years will have 14 study visits.


Sickle cell disease (SCD) is a multisystem disorder associated with episodes of acute clinical events and progressive organ damage. Episodic pain, triggered by microvascular vaso-occlusion induced by sickling of red blood cells (RBCs), is the most common acute complication and the leading cause of hospitalization. As the root cause of SCD is polymerization of deoxy-hemoglobin S (HbS), there is a strong rationale for exploring agents that could inhibit or reduce the polymerization process itself. HbS polymerization is influenced by a number of factors, including 2,3-diphosphoglycerate (2,3-DPG) concentration in the RBC. Increased 2,3-DPG levels in SCD decrease oxygen binding of hemoglobin and stabilizes the deoxygenated state, causing HbS to polymerize. In addition, increased 2,3-DPG concentration decreases intraerythrocyte pH, further promoting HbS polymerization. 2,3-DPG is an intermediate substrate in the glycolytic pathway, the only source of energy production in RBCs in the form of adenosine triphosphate (ATP). Pyruvate kinase (PK) is a key enzyme in the final step of glycolysis that is responsible for 50% of the total red cell ATP production. ATP is essential for maintaining integrity of the RBC membrane, and therefore reduced PK activity not only leads to the accumulation of upstream 2,3-DPG and HbS polymerization but also affects RBC membrane health. Therefore, increasing red cell PK (PKR) activity presents a new and potentially attractive therapeutic target for thwarting HbS polymerization, vaso-occlusion, and hemolysis in SCD.

Mitapivat (AG-348) is an orally bioavailable small molecule allosteric activator of PKR, currently being studied in Phase II/III clinical trials in humans with PK deficiency (NCT02476916, NCT03548220 / AG348-C-006; NCT03559699 / AG348-C-007), as well as in an ongoing Phase II clinical trial in humans with non-transfusion-dependent thalassemia (NCT03692052). The recently published results of mitapivat treatment in a large cohort of PK deficient subjects appear promising, with demonstrated durable improvement in anemia and reduction in hemolysis, as well as an acceptable safety profile. The preclinical and clinical mitapivat data support dose-dependent changes in blood glycolytic intermediates including 2,3-DPG, consistent with glycolytic pathway activation at multiple ascending doses tested, supporting the potential anti-sickling role of mitapivat in the treatment of SCD.

We (PI: Dr. S. L. Thein) initiated a Phase I study (NCT04000165) to assess clinical safety and tolerability of multiple escalating doses of mitapivat in subjects with SCD. To date, we have observed an acceptable safety profile for mitapivat at all doses, as well as preliminary evidence of efficacy, with increases in hemoglobin level and decreases in hemolytic markers observed in a majority of SCD subjects. Following on these preliminary results, the present study has been initiated to evaluate the safety, tolerability, and efficacy of long-term treatment with maintenance dosing of mitapivat in subjects with SCD.

Condition Sickle Cell Disease, Hemolytic Anemia
Treatment Mitapivat
Clinical Study IdentifierNCT04610866
SponsorNational Heart, Lung, and Blood Institute (NHLBI)
Last Modified on21 September 2022


Yes No Not Sure

Inclusion Criteria

Subjects completing Study 19H0097 will first be screened for eligibility. Eligibility criteria are identical with the exception of criteria 1.4, 2.2, and 2.3.p. If any of the 15 subjects completing the 19H0097 study are unable to participate in or complete the current extension study (defined as completing 24 weeks of treatment with study drug to allow for assessment of the primary endpoint), then additional new subjects na(SqrRoot) ve to mitapivat treatment
may be enrolled to replace them
Subjects will enroll onto the study and undergo screening. Subjects who do not meet any of
the following criteria during screening will not receive the study intervention but will be
counted toward study accrual. Screen failures may be rescreened at a later time
In order to be eligible to participate in this study, an individual must meet all of the
following criteria
1 Have provided signed written informed consent prior to performing any study
2 Age between 18-70 years
procedure, including screening procedures
3 Unequivocal diagnosis of HbSS confirmed by hemoglobin electrophoresis performed on
5 Have adequate organ function, as defined by
patients at least 90 days after a blood transfusion if previously transfused, or DNA
4 No transfusion in the 12 weeks prior to signing consent, or absence of Hb A on
c. Absolute neutrophil count >=1.0 x 10^9power/L
hemoglobin analysis (by high-performance liquid chromatography; HPLC)
d. Hemoglobin >= 7 g/dL
e. Platelet count >=100 x 10^9/L
a. Serum aspartate aminotransferase (AST) <=2.5 x Upper Limit of Normal (ULN)
(unless the increased AST is assessed by the Investigator as due to hemolysis)
and alanine aminotransferase (ALT) <=2.5 x ULN
b. Serum creatinine <=1.25 x ULN. If serum creatinine is >1.25 x ULN, then
8 Be willing to comply with all study procedures for the duration of the study
glomerular filtration rate (based on creatinine) must be >=60 mL/min
f. Activated partial thromboplastin time and international normalized ratio <=1.5
x ULN, unless the subject is receiving therapeutic anticoagulants
6 For women of reproductive potential, have a negative serum pregnancy test during
the screening period. Women of reproductive potential are defined as sexually mature
women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal
occlusion; or who have not been naturally postmenopausal (i.e., who have not
menstruated at all for at least the preceding 1 year prior to signing informed consent
unrelated to hormonal contraception)
7 For women of reproductive potential as well as men and their partners who are
women of reproductive potential, be abstinent as part of their usual lifestyle, or
agree to use 2 effective forms of contraception from the time of giving informed
consent, during the study, and for 28 days (both men and women) following the last
dose of study treatment. An effective form of contraception is defined as hormonal
oral contraceptives, injectables, patches, intrauterine or subdermal contraceptive
implants, and barrier methods

Exclusion Criteria

1 Documented pyruvate kinase deficiency
2 Screening hemoglobin level of >= 11 g/dL
c. Cardiac dysrhythmias judged as clinically significant by the Investigator
f. History of drug-induced cholestatic hepatitis
j. Positive test for human immunodeficiency virus 1 or 2 Ab
q. Have had a prior bone marrow or stem cell transplant
r. Are currently pregnant or breastfeeding
3 Have a significant medical condition that confers an unacceptable risk to
participating in the study, and/or that could confound the interpretation of the study
data. Such significant medical conditions include, but are not limited to the
a. Poorly controlled hypertension (defined as systolic blood pressure [BP] >150
mmHg or diastolic BP >90 mmHg) refractory to medical management
b. History of recent (within 24 weeks prior to signing consent) decompensated
congestive heart failure; myocardial infarction or unstable angina pectoris
hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary
or arterial embolism
d. Heart-rate corrected QT interval-Fredericia's method (QTcF) >480 msec with the
exception of subjects with right or left bundle branch block
e. Clinically symptomatic cholelithiasis or cholecystitis. Prior cholecystectomy
is not exclusionary. Subjects with symptomatic cholelithiasis or cholecystitis
may be rescreened once the disorder has been treated and clinical symptoms have
g. Iron overload sufficiently severe to result in a clinical diagnosis by the
Investigator of cardiac (e.g., clinically significant impaired left ventricular
ejection fraction), hepatic (e.g., fibrosis, cirrhosis), or pancreatic (e.g
diabetes) dysfunction
h. Have a diagnosis of any other congenital or acquired blood disorder, or any
other hemolytic process as defined by a positive direct antiglobulin test (DAT)
except mild allo-immunization as a consequence of transfusion therapy
i. Positive test for hepatitis B surface antigen or hepatitis C virus (HCV)
antibody (Ab) with signs of active hepatitis B or C virus infection. If the
subject is positive for HCVAb, a reverse transcriptase-polymerase chain reaction
test will be conducted. Subjects with hepatitis C may be rescreened after
receiving appropriate hepatitis C treatment
k. Active infection requiring any use of systemic antimicrobial agents
(parenteral or oral) or Grade >=3 in severity (per National Cancer Institute
Common Terminology Criteria for Adverse Events) within 8 weeks prior to signing
l. Diabetes mellitus judged to be under poor control by the Investigator or
requiring >3 antidiabetic agents, including insulin (all insulins are considered
agent); use of insulin per se is not exclusionary
m. History of any primary malignancy, with the exception of: curatively treated
nonmelanomatous skin cancer; curatively treated cervical or breast carcinoma in
situ; or other primary tumor treated with curative intent, no known active
disease present, and no treatment administered during the last 3 years
n. Current or recent history of psychiatric disorder that, in the opinion of the
Investigator or Medical Monitor, could compromise the ability of the subject to
cooperate with study visits and procedures
o. Are currently enrolled in another therapeutic clinical trial involving ongoing
therapy with any investigational or marketed product or placebo. SCD subjects on
hydroxyurea or L-glutamine will also be considered, provided that they have been
on an unchanged dose of hydroxyurea or LGlutamine for 12 weeks prior to signing
consent. Use of the newer SCD therapies voxelotor or crizanlizumab will not be
permitted on this study, and subjects who have received voxelotor or
crizanlizumab in the 12 weeks prior to signing consent will be excluded
p. Have exposure to any investigational drug (other than the current drug
mitapivat), device, or invasive procedure within 12 weeks prior to signing
consent. All non-investigational invasive procedures within 12 weeks of signing
consent may be considered as a potential exclusion criteria per the PI s
s. Are currently receiving products that are strong inhibitors of CYP3A4/5 that
have not been stopped for (Bullet)5 days or a time frame equivalent to 5
half-lives (whichever is longer), or strong inducers of CYP3A4 that have not been
stopped for (Bullet)28 days or a time frame equivalent to 5 half-lives (whichever
is longer), prior to signing consent
t. Are currently receiving hematopoietic stimulating agents (e.g
erythropoietins, granulocyte colony stimulating factors, thrombopoietins) that
have not been stopped for a duration of at least 90 days prior to signing
u. Have a history of allergy to sulfonamides if characterized by acute hemolytic
anemia, drug-induced liver injury, anaphylaxis, rash of erythema multiforme type
or Stevens-Johnson syndrome, cholestatic hepatitis, or other serious clinical
v. Have a history of allergy to mitapivat or its excipients (microcrystalline
cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol)
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